Synthesis and pharmacological characterization of aminocyclopentanetricarboxylic acids: New tools to discriminate between metabotropic glutamate receptor subtypes

The four stereoisomers of 1-aminocyclopentane-1,3,4-tricarboxylic acid {ACPT-I (18) and -II (19), (3R,4R)-III [(-)-20], and (3S,4S)-III [(+)-20]} have been synthesized and evaluated for their effects at glutamate receptors subtypes. ACPTs are ACPD analogues in which a third carboxylic group has been added at position 4 in the cyclopentane ring. None of the ACPT isomers showed a significant effect on ionotropic NMDA, KA, and AMPA receptors. On the other hand, ACPT-II (19) was found to be a general competitive antagonist for metabotropic receptors (mGluRs) and exhibited a similar affinity for mGluRla (K-B = 115 +/- 2 mu M), mGluR2 (K-B = 88 +/- 21 mu M), and mGluR4a (K-B = 77 +/- 9 mu M), the representative members-of group I, II and III mGluRs, respectively. Two other isomers, ACPT-I (18) and (+)-(3S,4S)-ACPT-III [(+)-20], were potent agonists at the group III receptor mGluRAa (EC50 = 7.2 +/- 2.3 and 8.8 +/- 3.2 mu M) and competitive antagonists with low affinity for mGluR1a and mGluR2 (K-B > 300 mu M). Finally, (-)-(3R,4R)-ACPT-III [(-)-20] was a competitive antagonist with poor but significant affinity for mGluR4a (K-B = 220 mu M). These results demonstrate that the addition of a third carboxylic group to ACPD can change its activity (from agonist to antagonist) and either increase or decrease its selectivity and/or affinity for the various mGluR subtypes.